Cytotoxicity-boosting of kiteplatin by Pt(IV) prodrugs with axial benzoate ligands.
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| Abstract |
Kiteplatin, the neglected drug analogous of cisplatin but containing cis-1,4-DACH in place of the two ammines, has been recently reevaluated for its activity against cisplatin- and oxaliplatin-resistant tumors, in particular colo-rectal cancer. With the aim of further improving the pharmacological activity of this drug, Pt(IV) prodrugs were derived by addition of two, differently substituted, benzoate groups in axial positions (X-ray structure). The cytotoxic activity of both compounds resulted markedly potentiated reaching nanomolar concentration against a wide panel of human cancer cells. The ability of benzoate ligands to enhance the activity of kiteplatin most likely originates from their lipophilicity promoting a higher drug accumulation in cancer cells; however, it is to be noted that the increase in pharmacological effect is far greater than the increase in cellular uptake. Overcoming cisplatin- and oxaliplatin-resistance by kiteplatin derivatives appears to relate to the inability of membrane extrusion pumps to remove active Pt species from tumor cells.
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| Authors | Nicola Margiotta, Salvatore Savino, Cristina Marzano, Concetta Pacifico, James D Hoeschele, Valentina Gandin, Giovanni Natile |
| Journal | Journal of inorganic biochemistry (J Inorg Biochem) Vol. 160 Pg. 85-93 (07 2016) ISSN: 1873-3344 [Electronic] United States |
| PMID | 26775068 (Publication Type: Journal Article) |
| Copyright | Copyright © 2015 Elsevier Inc. All rights reserved. |
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